Inger Johansson, läkare, docent Sektionen för farmakogenetik, Institutionen för fysiologi och farmakologi, KI

Faktorer som påverkar hur stor effekten blir hos den enskilde patienten:

Absorption Effluxpumpar (p-pg) TUNNTARMEN: Metabolism (CYP3A4) LEVERN: Metabolism (flertal enzymer)

Polär molekyl Lipidlöslig molekyl Metabolism

Phase 1 Oxidation Hydroxylation Dealkylation Deamination Phase 2 Conjugation DerivateDrugConjugate

XXX OHO-konjugat Fas IFas II Cytokrom P450 Alkohol dehydrogenas Aldehyd dehydrogenas Xanthin oxidas Epoxid hydrolas UDP-glukuronosyltransferas Glutation S-transferas N-acetyltransferas Sulfotransferas Metyltransferas

Fas I-metabolism: oxidationer, reduktioner och hydrolyser Lever och även i viss mån tarmen. 1:a passageeffekt Högre dos behövs peroralt jmf andra admin.vägar. Uttalade interindividuella skillnader.

EfavirenzCyclophosphamidePropofol CYP3A4/5/7 CYP2E1 CYP2D6 * CYP2C19 * CYP2C9 * CYP2B6 * CYP1A2 TolbutamideWarfarinPhenytoinNSAIDBetablockersAntidepressantsAntipsychoticsDextromethorphanCodeineDebrisoquineDiazepamCitalopram Anti ulcer drugs ClozapineRopivacaine CyclosporinTaxolTamoxifenTacrolimusAmprenavir * 40 % of the phase I metabolism is carried out by polymorphic P450s AmiodaroneCerivastatinErythromycinMethadoneQuinine

Kodein Morfin CYP2D6 Ca 5 % Ej analgetisk effektAnalgetisk effekt Morfin Morfin-6-glukuronid UDP-glukuronosyl- transferas Aktivt LM Aktiv metabolit Analgetisk effekt

* Interindividual differences in drug metabolism 10 * genetic factors * drug-drug interactions * enzyme induction * dietary factors/inhibition * disease/inflammation * age

Kodein Morfin CYP2D6 Ca 5 % Ej analgetisk effektAnalgetisk effekt Morfin Morfin-6-glukuronid UDP-glukuronosyl- transferas Aktivt LM Aktiv metabolit Analgetisk effekt

Kodein metaboliseras till morfin av CYP2D6. PM (saknar CYP2D6) ingen analgetisk effekt, UM (extra mycket CYP2D6) kan få biverkningar Ammande mödrar som är CYP2D6 UM (ultrasnabba metaboliserare) kan produvera toxisk bröstmjölk efter intag av kodein! Madadi et al. Can Fam Physician :33-5

* Newborn male infant (birth weight 3,88 kg) * Difficulty breastfeeding and lethargy – 7 days old * Concerns skin colour and  milk intake – 11 days old * Cyanotic without vital signs – 13 days old * Morphine 70 mg/ml (10-12 ng/ml) * Mother recieved codeine (+ paracetamol) * Mother is carrier of duplicated CYP2D6 gene, i.e. 3 active CYP2D6 genes

Johansson et al., PNAS 90: , 1993 Aklillu et al., JPET 278: 441-6, 1996 *2x2 *2x3 *2x4 *2x5 *2x13

Steady state levels of nortriptyline as a function of the number of functional CYP2D6 genes Dalen et al

CYP2D6 and the European population Too rapid drug metabolism No drug response at ordinary dosage Non responders Too slow drug metabolism Too high drug levels at ordinary dosage High risk for ADRs No response from certain prodrugs (e.g. codeine) million people have CYP2D6 gene duplications (UMs) million people have no CYP2D6 enzyme (PMs)

S-warfarin 7-OH-warfarin CYP2C9 R-warfarin 6-OH-warfarin 8-OH-warfarin 10-OH-warfarin CYP3A4 CYP1A2 CYP1A1 oxidized vit K reduced vit K VKORC1 Vitamin K epoxide Reductase complex 1 NAD + NADH Hypofunctional factors II, VII, IX, X Protein C, S, Z Activated factors II, VII, IX, X Protein C, S, Z  -glutamyl carboxylase

Warfarin dosage variation: mg/day CYP2C9 25% prediction CYP2C9 + VKORC152% prediction 62% predictionCYP2C9 + VKORC1 + age and weight

Predictors: VKORC1 rs , CYP2C9 *2 and *3, age, gender and drug interactions. Wadelius et al. Blood 2008 Observed mean dose/week in the validation cohort Predicted mean dose/week

* Antiplatelet prodrug inhibiting the ADP-dependent P2Y12 receptor – bioactivation by CYP2C19 * Risks: sub-therapeutic (CD) or hyper- theraputic bioactivation (bleedings) * Second most selling drug in the world * Prevention of thrombotic events: * myocardial infarction * ischemic stroke * peripheral arterial disease * coronary stent placement * coronary syndrome Decreased bioactivation in carriers of defective CYP2C19 (CYP2C19*2) Increased bioactivation in CYP2C19*17 carriers Current view: FDA has included a black box warning to the label regarding reduced effectiveness in patients carrying two defective CYP2C19 alleles Medscape.org

CYP2C19 feno(geno)type PM (*2/*2) EM (*1/*1) UM (*17/*17) Clopidogrel bioactivation Platelet aggregation Platelet aggr. (ADP-induced) (AU*min) Stent thrombosis (%) TIMI bleedings (%) N/A Clopidogrel (Plavix) CYP2C19 genotype and clopidogrel treatment Based on Tiroch et al., 2010, Sibbing et al., 2010, Sibbing et al., 2009 Clopidogrel (Plavix) - antiplatelet Myocardial infarction Ischemic stroke Coronary stent placement Coronary syndromes FDA - Black Box Warning: Reduced effectiveness in patients carrying two defective CYP2C19 alleles (poor metabolizers) Bleedings OR=1.25 (95%CI; ) MACE OR=0.82 (95%CI; ) Meta analysis *17 carriers (coronary artery disease, CAD) N=9 428 Li et al 2011

Holmes et al., 2011, JAMA META analysis of CYP2C19-def and clopidogrel outcome 32 studies covering patients Incl of ”large enough” studies only (>200 events per study) Absolute risk of bleedings reduced by 5-8 events per subjects for carriers of CYP2C19-def alleles (RR=0.84; 95% CI, ) Increased risk of cardiovascular events; absolute relative risk increase of 8-12 events per subjects (RR=1.18; 95% CI, ) Medium size study inclusion (10—199 events per study) Increased risk for myocardial infarction as well as stent thrombosis; relative risks of 1.29 (95% CI, ) and 1.54 (95% CI, )

* A. Interaktionen har sannolikt ingen klinisk betydelse. * B. Interaktionens kliniska betydelse är ännu ej fastställd. * C. Interaktionen kan leda till ändrad effekt eller biverkningar men kan bemästras med individuell dosering och/eller plasmakon-centrationsbestämning av läkemedlet. Kombinationen kan kräva dosanpassning. * D. Interaktionen kan leda till allvarliga kliniska konsekvenser i form av svåra biverkningar, utebliven effekt eller är i övrigt svår att bemästra med individuell dosering. Kombinationen bör därför undvikas.

* De vanligaste olämpliga kombinationerna i D-klassen hos äldre pateinter är acetylsalicylsyra i lågdosberedning (Trombyl) tillsammans med antiinflammatoriska läkemedel av typen NSAID (ökad blödningsrisk).

* Förklaring till förra bilden * COX 1 och COX 2